CD4 T cells have long been thought to be orchestrators of the rest of the immune system, but the past decade of CD4 T cell research has revealed many new functions and new subsets of CD4 T cells such that the interactions between these subsets and the rest of the immune system in regards to viral pathogenesis need to be examined. We propose here a collaborative U19 program in response to RFA-AI-12-048, Immune Mechanisms of Virus Control. The work proposed is highly consistent with the aims of the RFA, including (1) examining the interactions between innate and adaptive immune mechanisms in viral systems, (2) examining such actions at mucosal sites, in this case the lung, (3) examining how different T and B cell subsets are maintained after infection, and (4) defining the impact of multiple infections on viral immunity and pathogenesis. This U19 studies viruses of interest to this RFA, including Group 1 (HHV-6), Group 3A (LCMV, vaccinia virus), and Group 3C (influenza virus) pathogens. Further, our program uses mouse models that have provided valuable information regarding the immune response to viral infections, and it translates these findings into human immunology. This program is directed by Dr. Raymond Welsh and involves already collaborating scientists within one department (Pathology) at the University of Massachusetts Medical School (UMMS). It consists of four research projects, one administrative core, and two scientific cores that will provide reagents to the projects as well as pursue novel technology development. Project 1 (Dr. Welsh) examines the ability of NK cells to act as natural suppressors of CD4 T cells and regulate B cells and CD8 T cell-dependent pathology and persistence in the lung; Project 2 (Dr. Swain) examines how memory CD4 T cells alter both innate and adaptive immunity to influenza A virus and contribute to long term antibody responses; Project 3 (Dr. Selin) examines how CD4 and CD8 T cells cross-reactive between different viruses mediate detrimental heterologous immunity in the lung in mouse models and in human influenza subjects; Project 4 (Dr. Stern) examines how human HHV-6-specific CD4 T cell responses regulate and are regulated by CD8 cells and NK cells. These highly collaborative projects will rely on a core B (Dr. Stern), which will provide MHC reagents for T cell analyses, and a core C (Dr. Huseby), which will provide T cell receptor cloning and transgenic mice. This program will be coordinated by an administrative Core A (Dr. Welsh), which will arrange meetings, consultations, resource sharing, and provide statistical analysis and data management. This work should provide insights into how to best harness these properties in the design of vaccine strategies. RELEVANCE: Infections of the respiratory track are among the leading cause of human illnesses, and they can be caused by many different viruses, which elicit strong immune responses and immunopathological lesions. This program project examines how CD4 T cells, considered the orchestrators of the immune system, interact with B cells, CD8 T cells, NK cells and the innate immune system to mediate or preclude virus-induced immunopathology. Knowledge gained form this study should help in the construction of vaccines and treatments for respiratory infections.